This competitive revision of P01 CA012582 "Surgery, Immunology and Immunotherapy of Human Cancer" describes a pivotal multicenter phase III trial that will compare surgery versus best medical therapy as initial treatment for patients with resectable stage IV melanoma. This will be the first multicenter prospective randomized comparison of surgical versus nonsurgical initial approaches. The trial's endpoints and infrastructure are based on the extensive trials of postoperative adjuvant immunotherapy performed under the parent grant, but its scope and clinico-economic impact are much broader. Comparative effectiveness research (CER) on this scale and for this subpopulation has never before been possible. The recent phase III trial of Canvaxin vaccine for stage IV melanoma found no significant benefit for the vaccine but demonstrated an unprecedented 40% rate of 5-year survival. This might reflect patient selection and/or Bacille Calmette-Guerin (BCG), which was used as an immune adjuvant in vaccine and placebo arms. The CER study described in this supplement will exploit the potential of BCG by including it in a 3-arm trial: surgery plus observation, surgery plus BCG, or best medical therapy for initial treatment of resectable stage IV melanoma. The first aim of this supplement is to initiate the landmark phase III randomized trial;we already have enthusiastic commitments and estimated accruals from U.S. sites that participated in the phase III Canvaxin trial. The second aim will begin correlative studies of serum markers and tumor volume doubling as prognostic factors. The third aim will strengthen and expand the Multicenter Trials Operation Center at JWCI for efficient management of the new phase III trial. This Center is already managing two other phase III melanoma trials (approximately 4400 patients) sponsored by JWCI. During the last 35 years, studies funded by P01 CA012582 have established the role of cytoreductive surgery and postoperative adjuvant immunotherapy for metastatic melanoma. Funding of this supplement will ensure uninterrupted progress of melanoma clinical research at centers across the country and accelerate the development of a comprehensive multidisciplinary paradigm for management of stage IV melanoma.